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Probing the Role of Protein Surface Charge in the Activation of PrfA, the Central Regulator of Listeria monocytogenes Pathogenesis

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Title: Probing the Role of Protein Surface Charge in the Activation of PrfA, the Central Regulator of Listeria monocytogenes Pathogenesis
Author(s): Xayarath, Bobbi; Volz, Karl W.; Smart, Jennifer I.; Freitag, Nancy E.
Subject(s): Listeria monocytogenes regulator
Abstract: Listeria monocytogenes is a food-borne intracellular bacterial pathogen capable of causing serious human disease. L. monocytogenes survival within mammalian cells depends upon the synthesis of a number of secreted virulence factors whose expression is regulated by the transcriptional activator PrfA. PrfA becomes activated following bacterial entry into host cells where it induces the expression of gene products required for bacterial spread to adjacent cells. Activation of PrfA appears to occur via the binding of a small molecule cofactor whose identity remains unknown. Electrostatic modeling of the predicted PrfA cofactor binding pocket revealed a highly positively charged region with two lysine residues, K64 and K122, located at the edge of the pocket and another (K130) located deep within the interior. Mutational analysis of these residues indicated that K64 and K122 contribute to intracellular activation of PrfA, whereas a K130 substitution abolished protein activity. The requirement of K64 and K122 for intracellular PrfA activation could be bypassed via the introduction of the prfA G145S mutation that constitutively activates PrfA in the absence of cofactor binding. Our data indicate that the positive charge of the PrfA binding pocket contributes to intracellular activation of PrfA, presumably by facilitating binding of an anionic cofactor.
Issue Date: 2011-08-12
Publisher: Public Library of Science
Citation Info: Xayarath, B., Volz, K. W., Smart, J. I., & Freitag, N. E. 2011. Probing the Role of Protein Surface Charge in the Activation of PrfA, the Central Regulator of Listeria monocytogenes Pathogenesis. PLoS One, 6(8): e23502. DOI: 10.1371/journal.pone.0023502.
Type: Article
Description: © 2011 Xayarath et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI: 10.1371/journal.pone.0023502.
URI: http://hdl.handle.net/10027/8429
ISSN: 1932-6203
Sponsor: This work was supported by Public Health Service grants AI41816 (NEF) from the National Institute of Allergy and Infectious Diseases (NIAID).
Date Available in INDIGO: 2012-08-07
 

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